The present invention addresses novel polycarboxylic ligand molecules and chelated complexes of said ligands with metals; the metals are for instance transition metals, e.g. paramagnetic metals for generating responses in the field of magnetic resonance imaging (MRI).
The present polycarboxylic ligands exhibit outstanding tensioactive properties which make them particularly useful in the form of paramagnetic chelates for making formulations and compositions useful as MRI contrast media of controllable and long lasting activity in the blood pool.
U.S. Pat. No. 5,466,438 (WO 92/231017) discloses compounds of formulae 
in which formulae I-III:
R1 is independently a substituted or unsubstituted C7-30 straight chain or cyclic compound;
R2 is independently a substituted or unsubstituted C1-C30 straight chain or cyclic compound which may be internally interrupted by O, NH, NR3 or S, where R3 is a C1-C3 alkyl;
n is 0-1 in formula I and 1-20 in formula III;
m is 1-2;
B is a substituted or unsubstituted C1-C30 straight chain or cyclic compound which may be internally interrupted by O, NH, NR3 or S.
In formula IV:
R1, R2 are independently H or a substituted or unsubstituted C7-C30 straight chain or cyclic compound;
R3, R4 are independently H or a substituted or unsubstituted C1-C30 straight chain or cyclic compound which may be internally interrupted by O, NH, NR5 or S, where R5 is a C1-C3 alkyl;
and in formula V:
R1 is independently a substituted or unsubstituted C7-C30 straight chain or cyclic compound
R2 is independently a substituted or unsubstituted C1-C30 straight chain or cyclic compound which may be internally interrupted by O, NH, NR4 or S, where R4 is a C1-C3 alkyl;
R3 is independently a substituted or unsubstituted C1-C30 straight chain or cyclic compound which may be internally interrupted by O, NH, NR4 or S, where R4 is a C1-C3 alkyl and
m is 0-12.
The reference also discloses contrast agents obtained with the compounds of the above formulae (I-V), the latter further comprising lipids; the lipids are in the form of emulsions, liposomes or micelles.
U.S. Pat. No. 5,312,617 dicloses a method of imaging comprising administering to patients a contrast agent comprising a complex of a paramagnetic metal and a ligand selected from formulae IV and V disclosed in the foregoing U.S. Pat. No. 5,466,438.
Liposomes incorporating the above chelates are also disclosed as well as the possibility of having the compounds in the form of emulsions or micelles.
The micelles can be prepared by a variety of conventional liposome preparatory techniques; suitable lipids include, for example, monomyristoyl-phosphatidyl-choline, monopalmitoyl-phosphatidylcholine, dibutyroyl-phosphatidylcholine and the like, linoleic acid, oleic acid, palmitic acid, and the like.
Lipid emulsions can be prepared by conventional techniques, for instance a typical method is as follows:
1. In a suitable flask, the lipids are dissolved in ethanol or chloroform or any other suitable organic solvent.
2. The solvent is evaporated leaving a thin layer of lipid at the bottom of the flask.
3. The lipids are resuspended in an aqueous medium, such as phosphate buffered saline, this producing an emulsion.
4. Sonication or microfluidization can then be applied to improve homogeneity.
5. The contrast agents can be added to the lipids during preparation of the emulsion, or they may be added to the emulsion afterwards.
6. Useful additives include, for example, soybean lecithin, glucose, Pluronic F-68 and D,L-xcex1-tocopherol; these additives are particularly useful where injectable intravenous formulations are desired.
The foregoing contrast agents may further comprise suspension stabilizers such as polyethyleneglycol, lactose, mannitol, sorbitol, ethyl alcohol, glycerin, lecithin, polyoxyethylene sorbitan monoleate, sorbitan monoleate and albumin. Various sugars and other polymers may also be added, such as polyethylene glycol, polyvinylpyrrolidone, polypropylene glycol and polyoxyethylene.
The contrast agents of this reference have high T1 and T2 relaxivity, especially when lipids are also present. Because of the high relaxivity, these contrast media are particularly useful for imaging the blood pool.
Despite the merit of the paramagnetic polycarboxylic chelates of the prior art as contrast agents for MRI, there was a need for a new range of chelating compounds of further improved properties designed to provide blood-pool contrast agents of outstanding long life in the circulation. In view of their structure including strongly hydrophobic and hydrophilic moieties, the compounds of the present invention achieve a significant step in the right direction.
The novel compounds of the present invention, either racemaic or enantiomeric have the following formulae (xe2x80xa0) and (IV) 
in which n and m are 1 or 0 but not simultaneously 1, and
when n=m=0, Rxe2x80x2 is H, and R* is a C12-25 linear or ramified, saturated or unsaturated, hydrocarbon radical;
when n=1 and m=0, R* is H or a C1-3 alkyl or alkylene substituent; and Rxe2x80x2 is selected from xe2x80x94NHR3, xe2x80x94NR4R5 and xe2x80x94OR6 where the R3 to R6 are independently C1-25 linear or ramified, saturated or unsaturated, hydrocarbon radicals optionally interrupted by xe2x80x94COxe2x80x94 and/or xe2x80x94Oxe2x80x94 and optionally terminated by xe2x80x94NR7R8 in which R7 and R8 are independently H or C12-25 hydrocarbon radicals;
when n=0 and m=1, R* is H or a C1-3 alkyl or alkylene substituent; and Rxe2x80x2 is selected from R9 and xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94R9 in which R9 is a C10-30 linear or ramified, saturated or unsaturated, hydrocarbon radical optionally interrupted by xe2x80x94NHxe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94COxe2x80x94 or xe2x80x94Oxe2x80x94, R10 being a lower aliphatic hydrocarbon; and
R12 is H or a C12-30 hydrocarbon radical optionally interrupted by xe2x80x94NHxe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94COxe2x80x94 or xe2x80x94Oxe2x80x94 and optionally terminated by a cholesteryl residue, and the R13 are xe2x80x94OH; or one or two R13 are a xe2x80x94NHxe2x80x94 R14 group in which R14 is a C2-30 linear or ramified, saturated or unsaturated, hydrocarbon radical optionally interrupted by xe2x80x94NHxe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94, and/or xe2x80x94OPO(OH)Oxe2x80x94, the remaining R13 being xe2x80x94OH.
The compounds of formulae (xe2x80xa0) and (IV) can be used as chelates of paramagnetic metals, preferably Gd(III), Mn(II), Cr(III), Cu(II), Fe(III), Pr(III), Nd(III), Sm(III), Tb(III), Yb(III), Dy(III), Ho(III) and Er(III) in the preparation of MRI contrast formulations and compositions of outstanding long life in the blood which makes them ideal agents for investigating the circulation in appended organs.
Preferred are the compounds encompassed by formula (xe2x80xa0), in which n and m are 1 or 0 but not simultaneously 1, and when n=1 and m=0, R* is an alkylene group, and the other variable groups are the meanings defined above.
Equally preferred are the compounds encompassed by formula (xe2x80xa0), in which n and m are 1 or 0 but not simultaneously 1, and when n=1 and m=0, R* is H or a C1-3 alkyl; and Rxe2x80x2 is selected from xe2x80x94NHR3, or xe2x80x94NR4R5, where the R3 to R5 groups are independently C12-25 linear or ramified, saturated or unsaturated, hydrocarbon radicals, optionally interrupted by xe2x80x94COxe2x80x94 and/or xe2x80x94Oxe2x80x94 and optionally terminated by xe2x80x94NR7R8 in which R7 and R8 are independently H or C12-25 hydrocarbon radicals with the same meaning just above defined.
Equally preferred are the compounds encompassed by formula (xe2x80xa0), in which n and m are 1 or 0 but not simultaneously 1, and when n=0 and m=1, R* is an alkylene group, and the other variable groups are the meaning defined above.
Equally preferred are the compounds encompassed by formula (xe2x80xa0), in which n and m are 1 or 0 but not simultaneously 1, and when n=1 and m=0, R* is H or a C1-3 alkyl; and Rxe2x80x2 is selected from R9 and xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94R9 in which R9 is a C12-25 linear or ramified, saturated or unsaturated, hydrocarbon radical optionally interrupted by xe2x80x94NHxe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94COxe2x80x94 or xe2x80x94Oxe2x80x94, R10 being a C1-4 linear or ramified, saturated or unsaturated, hydrocarbon radical.
Furthermore the preferred compounds are of general formula (IV) in which R12 is H, and two R13 are a xe2x80x94NHxe2x80x94R14 group in which R14 is a C12-25 linear or branched, saturated or unsaturated, hydrocarbon radical optionally interupted by xe2x80x94NHxe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94, and/or xe2x80x94OPO(OH)Oxe2x80x94, the remaining R13 being xe2x80x94OH.
The compounds of formula (xe2x80xa0) are preferably selected among compounds of the following formulae (I), (II) or (III) 
wherein R* is as defined heretofore;
R is H or a C1-3 alkyl or alkylene substituent;
R1 is selected from xe2x80x94NHR3, xe2x80x94NR4R5 and xe2x80x94OR6 where the R3 to R6 are independently C1-25 linear or ramified, saturated or unsaturated, hydrocarbon radicals optionally interrupted by xe2x80x94COxe2x80x94 and/or xe2x80x94Oxe2x80x94 and optionally terminated by xe2x80x94NR7R8 in which R7 and R8 are independently H or C12-25 hydrocarbon radicals;
R2 is selected from R9 and xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94R9 in which R9 is a C10-60 linear or ramified, saturated or unsaturated, hydrocarbon radical optionally interrupted by one or more xe2x80x94NHxe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94COxe2x80x94 or xe2x80x94Oxe2x80x94, R10 being a lower aliphatic hydrocarbon.
For instance, the compounds of formula (II) can have formula (IIa) 
in which R3 is a C12-25 linear or ramified, saturated or unsaturated, hydrocarbon radical.
Particularly preferred are the compounds of formula (IIa) in which R3 is a C16-20 linear or ramified, saturated or unsaturated, hydrocarbon radical.
Or they can have formula (IIb) 
in which R4 and R5 are independently C12-25 linear or ramified, saturated or unsaturated, hydrocarbon radicals optionally interrupted by xe2x80x94COxe2x80x94 and/or xe2x80x94Oxe2x80x94.
Particularly preferred are the compounds of formula (IIb) in which R4 and R5 are independently C16-20 linear or ramified, saturated or unsaturated, hydrocarbon radicals interrupted by xe2x80x94COxe2x80x94 and xe2x80x94Oxe2x80x94.
Furthermore, they can have formula (IIc) 
in which A is xe2x80x94NHxe2x80x94 or xe2x80x94Oxe2x80x94, A1 is a C1-20 linear or ramified, saturated or unsaturated, hydrocarbon radicals optionally interrupted by xe2x80x94COxe2x80x94 and/or xe2x80x94Oxe2x80x94 and R7 and R8 are defined as above.
Particularly preferred are the compounds of formula (IIc) in which R is an alkylene substituent.
Equally preferred are the compounds of formula (IIc) in which A is xe2x80x94NHxe2x80x94, A1 is a C1-20 linear or ramified, saturated or unsaturated, hydrocarbon radicals interrupted by xe2x80x94COxe2x80x94 and xe2x80x94Oxe2x80x94 and R7 and R8 are defined as above. Also the compounds of formula (IIc) are preferred in which A is xe2x80x94Oxe2x80x94 and A1 is a C1-20 linear or ramified, saturated or unsaturated, hydrocarbon radicals interrupted by xe2x80x94COxe2x80x94 and xe2x80x94Oxe2x80x94 and R7 and R8 are defined as above.
Compounds of formula (III) can have formula (IIIa) 
in which R is H and R2 is is a C10-30 linear or ramified, saturated or unsaturated, hydrocarbon radical optionally interrupted by one or more xe2x80x94NHxe2x80x94, xe2x80x94Nxe2x80x94, xe2x80x94COxe2x80x94 or xe2x80x94O. Otherwise, they can have formula (IIIb) below 
in which R is H and R9 is a C10-25 linear alkyl, or a C10-50 linear or ramified, saturated or unsaturated, hydrocarbon radical optionally interrupted by one or more xe2x80x94Nxe2x80x94, xe2x80x94COxe2x80x94 and/or xe2x80x94Oxe2x80x94.
Some preferred compounds of formula (IV) are those in which all the R13 are xe2x80x94OH and R12 is defined as mentioned above. Otherwise, compounds of formula (IV) can be selected from the compounds of formulae (IVa) and (IVb) below. In Formula (IVa), 
the R14 are independently as defined above for formula (IV).
Particularly preferred are the compounds of formula (Iva) in which R14 is Cl2-25 linear or ramified, saturated or unsaturated, hydrocarbon radical optionally interrupted by xe2x80x94COxe2x80x94 and/or xe2x80x94Oxe2x80x94, and/or xe2x80x94OPO(OH)Oxe2x80x94.
In formula (IVb) shown below, 
R14 is a C12-25 linear or ramified, saturated or unsaturated, hydrocarbon radical.
The compounds of this invention of formulae (xe2x80xa0) and (IV) can be as represented in the formulae; or they can be in the form of complex chelates with paramagnetic metal ions (as indicated heretofore) and the salts thereof with physiologically acceptable bases selected from primary, secondary, tertiary amines and basic aminoacids, or inorganic hydroxides of sodium, potassium, magnesium, calcium or mixtures thereof;
or with physiologically acceptable anions of organic acids selected from acetate, succinate, citrate, fumarate, maleate, oxalate, or inorganic acids selected from hydrogen halides, sulphates, phosphates, phosphonates and the like;
or with cations or anions of aminoacids selected from lysine, arginine, ornithine, aspartic and glutamic acids, and the like;
For preparing the compounds of formula (I) in the form of complexes with metals (ME), one can proceed as in the following Scheme 1: 
Where Pg is a protecting group;
R* is as defined for formula (I);
MEn+ is a metal ion;
n=2 or 3.
In step a1 the compound 1A, i.e. 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, whose carboxylic groups are suitably protected by groups such as benzyl or t-butyl, is reacted with R*xe2x80x94X, where R* is a substituent residue and X is a leaving group such as Cl, Br, I. The reaction product is then deprotected by known methods (e.g. with CF3COOH) to give the free ligand 1B. The ligand is then complexed with a suitable metal ion oxide or salt (preferably paramagnetic), such as Gd oxide, chloride or acetate, in order to obtain the desired metal complex chelate 1C. Depending on the value of n, 1C may be salified with a suitable counter-ion.
For the complexes of the compounds of formula (IIa), one may proceed according to the scheme 2 below: 
in which Pg is a protecting group as in Scheme 1;
R and R3 have been defined above; and ME and n are as in Scheme 1.
According to the method of Scheme 2, one prepares compound 2C by the reaction of a halogenated halide (or equivalent) with a primary amine R3NH2 in a suitable solvent, such as CH2Cl2, CHCl3 or H2O/CH2Cl2 mixtures, in the presence of a base (e.g. K2CO3). Then, Compound 2C is reacted with compound 2D and the product is deprotected (b2) to furnish the desired free ligand 2E. The latter is finally complexed according to the general procedure disclosed in Scheme 1. If required, i.e. depending on whether n has an appropriate value, compound 2F may be salified with a suitable counter-ion.
For preparing the metal complexes of the compounds of formula (IIb), one may proceed according to the Scheme 3 below: 
in which n=1-6; p=0-5; m=2 or 3; Y=halogen; Pg is a protecting group and Alk is a lipophilic alkyl chain.
In step a3 compound 3A is reacted with a suitable long-chain carboxylic acid halide 3B in a suitable aprotic dipolar solvent to obtain compound 3C. The latter is reacted (step b3) with compound 3D, i.e. 1,4,7,10-tetraaza-cyclododecane-1,4,7,10-tetraacetic acid of which three acetic groups are protected with, for example, benzyl or t-butyl groups, in the presence of 1-propanephosphonic acid cyclic anhydride (PPAA) and a base (e.g. Et3N) in a suitable solvent such as CH2Cl2.
Compound 3E obtained in step c3 is deprotected by known methods (e.g. by catalytic hydrogenation) which provides the free ligand 3F, which is then complexed with a metal (step d3), according to the procedure described earlier. This affords the desired complex chelate 3G. Then, compound 3G may be salified with a suitable counter-ion if the value of m permits.
For preparing the compounds of formula (Iic) in which A is xe2x80x94NHxe2x80x94, one can proceed like in the previous scheme, the first step (condensation of triprotected 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (4A) with an amine H2N-A1-NR7R8 (4B) being effected in the presence, as condensing a agent, of (benzotriazo-1-yloxy)-tris(dimethylamino)-phosphonium hexafluorophosphate and a sterically hindered tertiary amine such as diisopropylethylamine (DIEA) when 4B is an a-aminoacid derivative, or N,Nxe2x80x2-bis(2-oxo-3-oxazolidyl)-phosphoro-diamidic chloride (BOP). This is illustrated in Scheme 4. 
A similar method can be applied for compounds (IIc) in which A is xe2x80x94Oxe2x80x94, i.e. the esterification of triprotected 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid with a halogenated compound Xxe2x80x94A1xe2x80x94NR7R8 in the presence of 1,8-diazabicyclo[5.4.0]undecene. Then the resulting intermediate 5C is deprotected, complexed and salified as in the previous schemes (Scheme 5). 
The compounds of formula (IIIa) can be obtained as illustrated in Scheme 6. The protected 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid 6A is reacted with an alkyl epoxide 
in a solvent such as ethanol and the resulting product is deprotected and treated as described in the previous schemes 
A possible technique for making the compounds (IIIb) and the corresponding metal chelates and salts is illustrated in Scheme 7. Here the initial reactant to be condensed with the triprotected 1,4,7,10-tetraaza-cyclododecane-1,4,7-triaacetic acid is 2,3-epoxypropanol 7B which provides the vic-diol 7C, the primary xe2x80x94OH of which is thereafter esterified with an acid R9-COOH, the remaining steps being as described previously. 
The following preparative methods are applicable regarding the compounds of formula (IV) in which R12 is H. For instance, for the compounds (IVa), one may operate as illustrated in Scheme 8, by reacting in DMF the DTPA cyclic, dianhydride (N,N-bis[2-(2,6-dioxo-4-morpholinyl)ethyl]gly-cine) 8A with an amine H2NR14, the remaining step being that of complexation with a metal and possible salification as discussed earlier. 
Otherwise, one may first effect protection of up to four of the xe2x80x94COOH""s groups in DTPA, the unprotected group being thereafter amidated in DMF with an amine H2NR14 according to usual means (see Scheme 9). 
One preparative route for the compounds of formula (IV) with a substituent R12 in xcex1- to the central carboxylic function is to first attach in the said position, a carbon chain functionalized with, for example, a xe2x80x94NH2 or xe2x80x94COOH group (Scheme 10). For example, compound 10A can be prepared, according to Rapoport et al. in J. Org. Chem. 58 (1993), 1151-1158, or using a method disclosed in WO 98/05626. The synthon is then reacted with, for example, a chloride of a carboxylic acid having the desired chain length, or with a suitable amine, depending on the nature of the said functional group. Then, the resulting compound 10B is deprotected and complexed as already shown in the previous Schemes. 
This technique is exemplified in the synthesis of the compound of Example 16 involving reaction with cholesteryl chloroformate.
The injectable compositions and formulations according to the invention which are usable as contrast agents for MRI investigations will preferably contain further additives, in addition to one or more of the afore discussed novel paramagnetic chelates and a carrier liquid. The additives include non-ionic and/or ionic surfactants and mixtures thereof, as well as other amphipatic compounds. Due to their physiological suitability, the non-ionic surfactants are preferred. The non-ionic surfactants are preferably block-copolymers having polyoxyethylene and polyoxypropylene sequences, polyethyleneglycol-alkylethers such as, for example, polyethyleneglycol-octadecylether, or polyoxyethylene fatty acid esters or polyoxyethylene sorbitan fatty acid esters, or n-alkyl glycopyranoside and n-alkyl maltotrioside. The non-ionic surfactant in the compositions of the invention is conveniently selected from the commercially available products, such as Pluronic(copyright), Poloxamer(copyright), Poloxamine(copyright), Synperonic(copyright), BRIJ(copyright), Myrj(copyright), Tween(copyright)s (polysorbates) and their mixtures. The weight proportion of the surfactant relative to the amount of the paramagnetic imaging agent is from 1:50 to 50:1, preferably 1:10 to 10:1, and even more preferably 1:1. The ionic surfactants preferably include biliary acid salts such as sodium deoxycholate.
The amphipatic compounds suitable in the present compositions are phospholipids which may be selected from phosphatidic acid (PA), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylglycerol (PG), phosphatidylinositol (PI), cardiolipin (CL) and sphyngomielin (SM). The amphipatic compound may also consists of a monophosphate ester of a substituted or partially substituted glycerol, at least one functional group of said glycerol being esterified by saturated or unsaturated aliphatic fatty acid, or etherified by saturated or unsaturated alcohol, the other two acidic functions of the phosphoric acid being either free or salified with alkali or earth-alkali metals. Preferably the phosphate esters will include monophosphates of fatty acid glycerides selected from dimiristoylphosphatidic acid, dipalmitoylphosphatidic acid, or distearoylphosphatidic acid.
The phospholipids may also include diacyl and dialkyl glycerophospholipids in which the aliphatic chains have, at least twelve carbon atoms, as well as one or more compounds selected from ionic and neutral phospholipids, monoalkyl or alkenyl esters of phosphoric acid and/or cholesterol, ergosterol, phytosterol, sitosterol, lanosterol, tocopherol. In the compositions containing phospholipids, the weight proportion of the phospholipids to the amphiphilic chelate seems not critical and it may vary, for example, from 1:50 to 50:1. The practical range will be between 10:1 and 1:10, preferably between 1:5 and 5:1 and even more preferably between 1:3 and 3:1. In the compositions in which phospholipids are used the weight ratio of the phospholipid to the surfactant may vary as above, however the ranges from 1:10 to 10:1 and, preferably, between 1:2 and 2:1 are considered optimal.
The compositions of the present invention may exist in micellar form, in which case they can be prepared using known techniques, namely as described in WO 97/00087; Polym. Prepr. 1997, 38(1), 545-546; Acad. Radiol. 1996, 3, 232-238. These documents describe micelles of amphiphilic Gd chelates useful in percutaneous lymphography. The micelles have particle size between 10 and 500 nm, preferably between 50 and 200 nm.
The micelles can be prepared in any physiologically acceptable aqueous liquid carrier, such as water or saline, neat or bufferd, according to usual practice. Depending upon the choice of the components, the dispersion can be achieved by gentle mixing or by more energetic means, such as homogenisation, microfluidization or sonication.
In an advantageous mode of preparing the micelles of the invention, one part by weight of the paramagnetic chelate contrast component is admixed with one to two parts each of surfactants and of lipids, and with 100 to 200 parts of liquid carrier, for example Tris/Glycerol buffer.
The compositions can be stored and used as such, or may be lyophilized dry, according to known methods, e.g. by freeze-drying. This dry form (porous lumps or free flowing powder) is particularly convenient for long-term storage. The formulations can be reconstituted before usage by dispersion of the lyophilizate in a physiologically acceptable liquid carrier, thus obtaining a suspension corresponding to the early formulation and directly usable as NMR imaging contrast agent.
For practically applying the compositions of the invention in the medical field, the lyophilized components and the carrier liquid can be marketed separately in a kit form. The lyophilized components may be stored under a dry, inert atmosphere and the carrier liquid may further contain isotonic additives and other physiologically acceptable ingredients, such as various mineral salts, vitamins, etc.
The compositions of the invention are particularly useful as magnetic resonance contrast agents for the imaging of the blood pool. They have shown to possess a sufficiently high relaxivity effect on the blood after injection in the rat and an exceptionally favourable elimination kinetic profile from the blood circulation, as demonstrated by pharmacokinetic and biodistribution data. These two combined characteristics make them very suitable for angiographic magnetic resonance imaging in general. The compositions of the invention can therefore facilitate MR angiography and help to assess myocardial and cerebral ischemia, pulmonary embolism, vascularization of tumours and tumour perfusion.